Pulmonary embolism (PE) results in at least 630,000 symptomatic episodes in the United States yearly, making it about half as common as acute myocardial infarction, and three times as common as cerebrovascular accidents.¹ Acute PE is the third most common cause of death (after heart disease and cancer). Estimates of PE are probably low because approximately 75% of autopsy-proved PE are not detected clinically² and in 70 to 80% of the patients in whom the primary cause of death was PE, premortem diagnosis was completely unsuspected.^3,4 Of all hospitalized patients who develop PE, 12 to 21% die in the hospital, and another 24 to 39% die within 12 months.^5-7 Thus, approximately 36 to 60% of patients who survive the initial episode live beyond 12 months, and may present later in life with a wide variety of symptoms.

In addition, approximately 2.5 million Americans develop deep vein thrombosis (DVT) each year, and more than 90% of clinically detected pulmonary emboli are associated with lower extremity DVT. However, in two-thirds of patients with DVT and PE, the DVT is asymptomatic.^8-10

For the most part, DVT and acute PE are managed medically. Cardiac surgeons rarely become involved in management of acute PE, unless it is in a hospitalized patient who survives a massive embolus that causes life-threatening acute right heart failure with low cardiac output, with a large clot burden. On the other hand, the mainstay of treatment for patients with chronic pulmonary thromboembolic disease¹¹ is the surgical removal of the disease by means of pulmonary thromboendarterectomy. Medical management for this condition is only palliative, and surgery by means of transplantation is an inappropriate use of resources with outcomes inferior to thromboendarterectomy.

Deep vein thrombosis primarily affects the veins of the lower extremity or pelvis. It is most common in hospitalized patients but may occur in ambulatory patients outside the hospital.^12,13 The process may involve superficial as well as deep veins, but superficial venous thrombosis does not generally propagate beyond the saphenofemoral junction and therefore very rarely causes PE.^9,14,15 Venous thrombosis of the upper extremity is almost always associated with trauma, indwelling catheters, or other pathologic states and is an uncommon cause of PE, but can be fatal. Pulmonary emboli that do not originate from the deep venous system of the legs, pelvis, or arms are thought to come from a diseased right atrium or ventricle or retroperitoneal and hepatic systems.^12,13

Pathogenesis

In 1856, Rudolf Virchow made the association between DVT and PE and suggested that the causes of DVT were related to venous stasis, vein wall injury, and hypercoagulopathy. This triad of etiologic factors remains relevant today and is supported by an ever-growing body of evidence.

Immobilization is by far the most important cause of venous stasis in hospitalized patients. Injections of contrast material in foot veins require up to 1 hour to clear from the venous valves in the soleus muscle of immobilized patients.¹⁶ Venous stasis may also be produced by mechanical obstruction of proximal veins, by low cardiac output, by venous dilatation, and by increased blood viscosity.¹⁷ Some pelvic tumors, bulky inguinal adenopathy, the gravid uterus, previous caval or iliac venous disease, and elevated central venous pressures from cardiac causes also enhance venous stasis.

The role of vein wall injury is less clear because DVT often begins in the absence of mechanical trauma. Recent work shows that subtle vein wall injuries may occur during operation in veins remote from the operative field.^18,19 In animals, endothelial cell tears have been found at junctions of small veins with larger veins at remote sites during hip replacement (Fig. 52-1).

Three uncommon familial deficiencies associated with venous thrombosis are seen in antithrombin, protein C, and protein S. Antithrombin is a natural plasma protease that inhibits thrombin after it is formed, and to a lesser extent before it is formed. Antithrombin is also the cofactor that is accelerated 1000-fold by heparin. Protein C is a potent inhibitor of factor V and platelet-bound factor VII and requires protein S as a cofactor for anticoagulant activity. Both protein C and S are vitamin-K–dependent zymogens that are activated by thrombin and accelerated by thrombomodulin produced by endothelial cells.^20,21

A much more common coagulation deficiency, resulting from a mutation of factor V (factor V Leiden) that prevents its degradation by protein C, has been described and is present in approximately 6 to 7% of study populations of Swedes and North American males.^22-24 Both the homozygous and heterozygous mutants are strongly associated with venous thrombosis and PE but are not associated with manifestations of arterial thrombosis.^24,25

The presence of the lupus anticoagulant, which is an acquired IgG or IgM antibody against prothrombinase, increases the likelihood of venous thrombosis by poorly understood mechanisms.²⁵ The disease may be associated with lupus-like syndromes, immunosuppression, or intake of specific drugs, such as procainamide.

Risk Factors for Deep Vein Thrombosis

Table 52-1 presents a list of major risk factors for the development of DVT or PE. Previous thromboembolism, older age, immobilization for more than 1 week, orthopedic surgery of the hip or knee, recent surgery, multiple trauma, and cancer are strong risk factors. In patients with a history of venous thromboembolism the risk of developing a new episode during hospitalization is nearly eight times that of someone without a history.^9,26-29 Up to 10% of patients with a first episode of DVT or PE and up to 20% of those with a recurrent event develop a new episode of venous thromboembolism within 6 months.³⁰

The incidence of DVT and PE increases exponentially with age (Fig. 52-2). Males are at greater risk than females. Prolonged bed rest or immobility from any cause are major risk factors. Although usually other risk factors are present, the incidence of autopsy-proved venous thrombosis rises from 15 to 80% in patients at bed rest for more than 1 week.^30,31

The incidence of venous thromboembolism increases threefold in patients who have operations for cancer.⁹ Of particular interest to cardiac surgeons and cardiologists is the observation that clinically silent DVT develops during hospitalization in nearly 50% of patients after myocardial revascularization.³²

A follow-up study³³ found that the incidence of PE in hospital after coronary arterial bypass operations was 3.2% and hospital mortality in patients with PE was 18.7%. Interestingly, valvular surgery was not associated with the development of PE. In a retrospective study of 5694 patients who had open heart surgery, Gillinov and colleagues found the risk of PE proved by V/Q scan (20 patients), angiography (four patients), or autopsy (eight patients) was 0.56% within 60 days. The mortality was 34% in patients with PE.³⁴

Diagnosis

Approximately two-thirds of patients with DVT do not have clinical symptoms;⁹ therefore, the diagnosis depends on a high degree of clinical suspicion and a variety of objective diagnostic tests. Venography remains the most reliable test for detecting thrombus in calf veins, but is invasive, not suitable for serial studies, and the contrast material may be thrombogenic if allowed to remain within the deep venous system.¹⁰

The most popular noninvasive test, which can be done at the bedside, is a combination of ultrasound and color flow Doppler mapping, widely referred to as duplex scanning. The method does not detect fresh thrombi directly but infers the presence of clot by flow patterns and the inability to compress the vessel in specific locations.¹⁰ In the hands of skilled examiners duplex scanning is highly accurate for the detection of thrombus in popliteal, deep femoral, and superficial femoral veins and has a sensitivity between 89 and 100% against venography in symptomatic patients. Magnetic resonance imaging (MRI) is a noninvasive method that can image the entire venous system, including upper extremity veins and mediastinum.³⁵ Against MRI duplex scanning has a sensitivity of 70% for pelvic veins and a specificity of nearly 100%.³⁶ Impedance plethysmography assesses volume changes in the leg after occlusion of the vein with calf electrodes and a thigh cuff. It is clinically useful in symptomatic patients but has relatively low sensitivity and specificity in asymptomatic patients and calf thrombosis.³⁶ Injection of iodine 125-labeled fibrinogen with subsequent leg scanning is a sensitive test for detecting calf vein thrombus but does not detect iliofemoral vein thrombosis. The combination of these two tests improves sensitivity and specificity, but in most hospitals duplex scanning, venography, and MRI have superseded both tests.

Prophylaxis

The prevalence of DVT, its strong association with PE, and the identification of risk factors in the pathogenesis of the disease provide the basis and rationale for prophylactic measures that are recommended in patients with two or more major risk factors, such as age over 40 years and major surgery.⁹ Innocuous measures such as compression stockings probably should be prescribed more often and be used in most nonambulating patients in the hospital. Intermittent pneumatic compression is more expensive and more cumbersome but is effective. Both methods reduce the incidence of DVT after general surgery to approximately 40% of control patients.⁹ Low-dose subcutaneous heparin and low-molecular-weight heparin given once a day reduce the incidence of DVT to approximately 35 and 18% of controls, respectively.^9,31,37 The reduction in PE with subcutaneous standard heparin or low-molecular-weight heparin is similar.^31,37

Calf vein DVT that does not propagate has a low risk of PE, and controversy exists as to whether or not these patients should be anticoagulated.¹⁵ Of patients who have DVT diagnosed in hospital without PE, the probability of clinically diagnosed PE within the next 12 months is 1.7%.⁵ If PE occurs, the probability of recurrent PE is 8.0%.⁵ Six months of warfarin anticoagulation is recommended for patients who have DVT with or without PE, as prophylaxis against recurrent disease.³⁸

Pathology and Pathogenesis

The only firm attachment of leg thrombus is at the site of origin, usually a venous saccule or venous valve pocket.²⁶ The degree of organization within the thrombus varies, but recent clots are more likely to migrate than older thrombi that are more firmly attached to the vessel wall.

Detached venous thrombi are carried in the bloodstream through the right heart into the pulmonary circulation. In autopsy series the percentage of emboli that obstruct two or more lobar arteries (major) ranges between 25 and 67% of all emboli; ³⁹ but this figure varies with the thoroughness of the examination. In clinical trials based on angiographic data the percentage of major emboli is similar and ranges from 30 to 64%.⁴⁰ The majority of pulmonary emboli lodge in the lower lobes,¹² and are slightly more common in the right lung than the left. This is probably the result of relative flow to those areas of the lung. Soon after reaching the lungs emboli become coated with a layer of platelets and fibrin.¹²

Simple mechanical obstruction of one or more pulmonary arteries does not entirely explain the often devastating hemodynamic consequences of major or massive emboli. Humoral factors, specifically serotonin, adenosine diphosphate (ADP), platelet-derived growth factor (PDGF), thromboxane from platelets coating the thrombus, platelet-activating factor (PAF), and leukotrienes from neutrophils are also involved.^41,42 Anoxia and tissue ischemia downstream from the emboli inhibit endothelium-derived relaxing factor (EDRF) production and enhance release of superoxide anions by activated neutrophils. The combination of these effects contributes to increased pulmonary vasoconstriction.⁴¹

Natural History

The mortality of a large, untreated PE is 18 to 33%, but can be reduced to about 8% if diagnosed and treated.^7,43,44 Seventy-five to ninety percent of patients who die of pulmonary emboli do so within the first few hours of the primary event.⁴⁵ In patients who have sufficient cardiopulmonary reserve and right ventricular strength to survive the initial few hours, autolysis of emboli occurs over the next few days and weeks.⁴⁶ On average, approximately 20% of the clot disappears by 7 days, and complete resolution may occur by 14 days.^44,46,47 For many patients, up to 30 days are needed to dissolve small emboli and up to 60 days for massive clots.⁴⁸ As the natural fibrinolytic system dissolves the embolic mass, the available cross-sectional area of the pulmonary arterial tree progressively increases, and pulmonary vascular resistance and right ventricular afterload decreases. In the vast majority of patients, pulmonary emboli continue to resolve and thus an immediate interventional therapy, particularly surgical embolectomy, is not necessary for survival except in a minority of patients.

In an unknown but small percentage of patients with acute PE the clot will not lyse, and chronic thromboembolic obstruction of the pulmonary vasculature develops. The reasons for failure of emboli to dissolve are unknown. Patients often are asymptomatic until symptoms of dyspnea, exercise intolerance, or right heart failure develop, mostly secondary to the pulmonary hypertension that ensues. Asymptomatic patients may have partial or complete chronic thrombotic occlusion of one or more segmental or lobar arteries. Symptomatic patients usually have more than 40% of their pulmonary vasculature obstructed by organized and fresh thrombi; however, significant pulmonary hypertension can develop in patients despite lesser degrees of vascular obstruction.

Clinical Presentation

Acute PE usually presents suddenly. Symptoms and signs vary with the extent of blockage, the magnitude of the humoral response, and the pre-embolus reserve of the cardiac and pulmonary systems of the patient.⁴⁹ Symptoms and signs vary widely, and in autopsy series of proven emboli only 16 to 38% of patients were diagnosed during life.³⁹

The acute disease is conveniently stratified into minor, major (submassive), or massive embolism on the basis of hemodynamic stability, arterial blood gases, and lung scan or angiographic assessment of the blocked pulmonary arteries.^40,49,50 Most pulmonary emboli are minor. These patients present with sudden, unexplained anxiety, tachypnea or dyspnea, pleuritic chest pain, cough, and occasionally streak hemoptysis.^39,45,50 Examination may reveal tachycardia, rales, low-grade fever, and sometimes a pleural rub. Heart sounds and systemic blood pressure are often normal; sometimes the pulmonary second sound is increased. Interestingly less than one-third of the patients will have evidence of clinical DVT.³⁹ Room air arterial blood gases indicate a PaO₂ between 65 and 80 torr and a normal PaCO₂ around 35 torr.⁴⁵ Pulmonary angiograms show less than 30% occlusion of the pulmonary arterial vasculature.

Major PE is associated with dyspnea, tachypnea, dull chest pain, and some degree of hemodynamic instability manifested by tachycardia, mild to moderate hypotension, and elevation of the central venous pressure.^45,50 Some patients may present with syncope rather than dyspnea or chest pain. In contrast to massive PE, patients with major embolism (at least two lobar pulmonary arteries obstructed) are hemodynamically stable and have adequate cardiac output.⁴⁰ Room air blood gases reveal moderate hypoxia (PaO₂ <65, >50 torr) and mild hypocarbia (PaCO₂ <30 torr).⁵⁰ Echocardiograms may show right ventricular dilatation. Pulmonary angiograms indicate that 30 to 50% of the pulmonary vasculature is blocked.

Massive PE is truly life-threatening and it causes hemodynamic instability.⁴⁰ It is usually associated with occlusion of more than 50% of the pulmonary vasculature, but may occur with much smaller occlusions, particularly in patients with preexisting cardiac or pulmonary disease. The diagnosis is clinical, not anatomical. Patients develop acute dyspnea, tachypnea, tachycardia, and diaphoresis; and sometimes may lose consciousness. Both hypotension and low cardiac output (<1.8 L/m²/min) are present. Cardiac arrest may occur. Neck veins are distended; central venous pressure is elevated, and a right ventricular impulse may be present. Room air blood gases show severe hypoxia (PaO₂ < 50 torr), hypocarbia (PaCO₂ < 30 torr), and sometimes acidosis.^40,45,50 Urine output falls; peripheral pulses are decreased and perfusion is poor.

Diagnosis

The clinical diagnosis of acute major or massive PE is wrong in 70 to 80% of patients who subsequently have angiography.^49,51 Even in postoperative patients and those with additional major risk factors for DVT, differentiation of major or massive PE from acute myocardial infarction, aortic dissection, septic shock, and other catastrophic states is difficult and uncertain.

The chest film may be normal but usually shows some combination of parenchymal infiltrate, atelectasis, and pleural effusion. A zone of hypovascularity or a wedged-shaped pleural-based density raises the possibility of PE. Usually, the ECG shows nonspecific T-wave or ST segment changes with PE. A minority of patients with massive embolism (26%) may show evidence of cor pulmonale, right axis deviation, or right bundle branch block.⁴⁹ An echocardiogram showing right heart dilatation raises the possibility of major or massive PE. A Swan-Ganz catheter generally shows pulmonary arterial desaturation (PaO₂ < 25 torr), but usually does not show pulmonary hypertension over 40 mm Hg because of low cardiac output and cor pulmonale (the unprepared right ventricle cannot generate pulmonary hypertension).

Ventilation-perfusion (V/Q) scans will provide confirmatory evidence, but these studies may be unreliable because pneumonia, atelectasis, previous pulmonary emboli, and other conditions may cause a mismatch in ventilation and perfusion and mimic positive results. In general, negative V/Q scans essentially exclude the diagnosis of clinically significant PE. V/Q scans usually are interpreted as high, intermediate, or low probability of PE to emphasize the lack of specificity but high sensitivity of the test (Fig. 52-3). Pulmonary angiograms provide the most definitive diagnosis, but collapse of the circulation may not allow time for this procedure, and pulmonary angiograms should not be performed if the patient’s circulation cannot be stabilized by pharmacologic or mechanical means.^52,53

MRI and CT angiography are better noninvasive methods for the diagnosis of pulmonary emboli and provide specific information regarding flow within the pulmonary vasculature.⁵⁴ Unfortunately, these methods are expensive, somewhat time consuming, and not widely available. Furthermore, they are not generally suitable for hemodynamically unstable patients. Transthoracic (TTE) or transesophageal (TEE) echocardiography with color flow Doppler mapping can provide reliable information about the presence or absence of major thrombi obstructing right-sided chambers or the main pulmonary artery. More than 80% of patients with clinically significant PE have abnormalities of right ventricular volume or contractility, or acute tricuspid regurgitation by TTE (Fig. 52-4).⁵⁵ In some patients, abnormal flow patterns can be discerned in major pulmonary arteries during TEE.

Management of Acute Major Pulmonary Embolism

For the purposes of this chapter, major or submassive PE is defined as an acute episode that causes hypoxia and mild hypotension (systolic arterial pressure > 90 mm Hg), but does not cause cardiac arrest or sustained low cardiac output and cardiogenic shock. By definition there is sufficient time in these patients to definitely establish the diagnosis and to attempt pharmacologic therapy and possibly remove the embolic material by catheter suction.

The first priority after sudden collapse of any patient is to establish adequate ventilation and circulation. The first may require intubation and mechanical ventilation. Pharmacologic agents, including cardiovascular pressors and vasoactive agents, are then used to help stabilize the patient’s hemodynamics. If the patient’s circulation can be stabilized, intravenous heparin is started with an initial bolus of 70 U/kg followed by 18 to 20 U/kg/h if there are no contraindications. Heparin will prevent propagation and formation of new thromboemboli, but does not dissolve the existing clot. In most instances the patient’s own fibrinolytic system lyses fresh thrombi over a period of days or weeks.⁴⁶

The addition of lytic therapy, that is, streptokinase, urokinase, or recombinant tissue plasminogen activator (rt-PA), increases the rate of lysis of fresh thrombi and is recommended in patients with a stable circulation and no contraindications. This increases the rate of lysis of fresh pulmonary clots over that of heparin alone during treatment,⁵⁶ but there is little difference in the amount of residual thrombus between the two treatments at 5 days or thereafter.^57-60 There is also no statistical difference in mortality or in the incidence of recurrent PE, but more recent experience shows a trend toward better results with thrombolytic therapy because of a more rapid reduction in right ventricular afterload and dysfunction.⁵⁶ Furthermore, there are no data that indicate that thrombolysis reduces the subsequent development of chronic pulmonary thromboembolism and pulmonary hypertension. Compared with Heparin therapy alone, thrombolytic agents carry a higher risk of bleeding complications, and despite precautions, bleeding complications occur in approximately 20% of patients.^56,61,62

Mechanical removal of pulmonary thrombi is possible by a catheter device inserted under local anesthesia into the femoral (preferred) or jugular vein.^50,63-66 Successful extraction of clot with meaningful reduction in pulmonary arterial pressure varies between 61 and 84%.^64,66

Management of Acute Massive Pulmonary Embolism

If the circulation cannot be stabilized at survival levels within several minutes or if cardiac arrest occurs after a massive PE, time becomes of paramount importance. Eleven percent of patients with fatal PE die within the first hour, 43 to 80% within 2 hours, and 85% within 6 hours.⁶⁷ To a great extent, circumstances and the timely availability of necessary equipment and personnel determine therapeutic options. A decision to treat medically in an effort to stabilize the circulation at a survival level may preempt life-saving surgery, but also may make surgery unnecessary. The relative infrequency of treatment opportunities in massive PE, mitigating factors, and the lack of clear criteria for prescribing medical or surgical therapy leave the management of massive PE unsettled.

When surgery is not immediately available, in patients who may not be surgical candidates, or in whom an alternate diagnosis seems more likely, emergency extracorporeal life support (ECLS) using peripheral cannulation is an attractive alternative.^68,69 In prepared institutions ECLS can be instituted rapidly outside the operating room. ECLS compensates for acute cor pulmonale and hypoxia and sustains the circulation until the clot partially lyses, pulmonary vascular resistance falls, and pulmonary blood flow becomes adequate.

Emergency Pulmonary Thromboembolectomy

Emergency pulmonary thromboembolectomy is indicated for suitable patients with life-threatening circulatory insufficiency, but should not be done without a definitive diagnosis because a clinical diagnosis of PE is often wrong.^47,58,65,70 If a patient has been taken directly to the operating room without a definitive diagnosis, TEE and color Doppler mapping can confirm or refute the diagnosis in the operating room. TEE will indicate increased right ventricular volume, poor right ventricular contractility, and tricuspid regurgitation, which are strongly associated with massive PE and acute cor pulmonale.⁷¹ Echocardiographic detection of a large clot trapped within the right atrium or ventricle in a hemodynamically compromised patient with massive acute PE is another indication for emergency pulmonary thromboembolectomy.^72-74

A midline sternotomy incision is used and cardiopulmonary bypass is initiated. The heart may be electrically fibrillated or arrested with cold cardioplegic solution. The main pulmonary artery is then opened 1 to 2 cm downstream to the valve, and the incision is extended into the proximal left pulmonary artery. Forceps and suction catheters are used to remove the clot from the left pulmonary artery and behind the aorta to the right pulmonary artery. If necessary the right pulmonary artery can also be exposed and opened between the aorta and superior vena cava to allow better exposure in the distal segments. If a sterile pediatric bronchoscope is available, the surgeon can use this instrument to locate and remove thrombi in tertiary and quaternary pulmonary vessels. Alternatively, the pleural spaces are entered, and each lung is gently compressed to dislodge small clots into larger vessels and suctioned out. Greenfield recommends placement of an inferior vena caval filter before closing the chest.^10,66,75,76 European surgeons generally clip the intrapericardial vena cava at the end of pulmonary thromboembolectomy to prevent migration of large clots into the pulmonary circulation.⁷⁴ However, this clip increases venous pressure and stagnant flow in the lower half of the body and causes considerable morbidity in more than 60% of patients.^72,74,75

Anticoagulation for 6 months is recommended for most patients with PE, but an inferior vena caval filter is recommended for patients with contraindications to anticoagulation or with recurrent PE, or those who will require pulmonary thromboendarterectomy. The cone-shaped Greenfield filter is the one most widely used and is associated with a lifetime recurrent embolism rate of 5% and has a 97% patency rate.⁷⁷

Extracorporeal Life Support

The wider availability of long-term extracorporeal perfusion (termed extracorporeal life support, ECLS) using peripheral vessel cannulation to stabilize the circulation offers a compromise position because most massive pulmonary emboli will dissolve in time. ECLS can be implemented outside the operating room within 15 to 30 minutes by an equipped team of trained personnel.^68,69

ECLS should not be needed beyond 1 to 2 days because clot lysis proceeds rapidly. Once pulmonary vascular resistance is adequately reduced, ECLS should be discontinued in the operating room as the femoral vessels will need to be surgically repaired because of the need for heparin and long-term anticoagulation.

Results

Mortality rates for emergency pulmonary thromboembolectomy vary widely between 40 and 92%.^66,72-75,78 Results are best if cardiopulmonary bypass is used to support the circulation during pulmonary arteriotomy.⁷³ The eventual outcome depends largely upon the preoperative condition and circulatory status of the patient. If cardiac arrest occurs and external massage cannot be stopped without ECLS, the mortality ranges between 45 and 75%. Without cardiac arrest mortality ranges between 8 and 36%.^72-74 ECLS instituted during cardiac resuscitation is associated with survival rates between 43 and 56%.^70,72 Recurrent embolism is uncommon,^75,79 and approximately 80% of survivors maintain normal pulmonary arterial pressures and exercise tolerance. In these patients postoperative angiograms are normal or show less than 10% obstructed vessels. A minority of patients have 40 to 50% of the pulmonary vessels obstructed and have significantly reduced exercise tolerance and pulmonary function.⁷⁹